This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Following infection with viruses such as HIV, antigens select specific lymphocytes from a large repertoire of T and B cells and induce them to selectively proliferate. These activated lymphocytes facilitate rapid antigen clearance and, upon neutralization of the pathogenic threat, they persist in the host as memory lymphocytes for a lifetime. The phenomenon of "original antigenic sin", first described in humans vaccinated against influenza virus, stands out as a paradox to Burnet's rules of B cell engagement. Humans previously exposed to influenza virus, upon infection with a novel influenza strain, produce antibodies directed primarily against the older viral strains at the expense of responses to novel protective antigenic determinants thus exacerbating the severity of the current infection. This blind spot of the immune system and the redirection of responses to the "original antigen," but not to novel epitopes in the current virus is a phenomenon which recent reports have questioned. Hence, we revisited this issue to determine the extent to which OAS is induced by variant influenza viruses. Using two related strains of influenza A viruses, we have shown that OAS can lead to a significant decrease in the development of immune memory and recall responses. In addition, we have shown that sequential infection of mice with live influenza virus strains leads to almost exclusive neutralizing antibody responses to the first viral strain suggesting that the induction of OAS could be a potential strategy by which variant influenza viruses subvert the immune system.